Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[C:6]([CH3:22])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1.[I-:24].[K+].II>C(O)C.CN.O>[CH3:1][C:2]1[C:3]([I:24])=[C:4]([OH:23])[CH:5]=[C:6]([CH3:22])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:20])[CH3:21])[CH:10]=1
Reactant: COCOc1ccc(Cc2c(C)cc(O)cc2C)cc1C(C)C
Reactant: [I-]
Agent: CN
Agent: II
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COCOc1ccc(Cc2c(C)cc(O)c(I)c2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (1.0 g, 3.18 mmol, Chiellini et al., Bioorg. Med. Chem. Lett. 10:2607 (2000)) in C2H5OH (30.0 mL) and 40% aqueous methylamine (6.20 mL) at 0° C. was added a solution of potassium iodide (2.5 g, 15.0 mmol) and iodine (0.98 g, 3.82 mmol) in H2O (6.20 mL). The reaction mixture was stirred at 0° C. for 1 h, quenched with water and extracted with ethyl acetate (2×30 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 20% ethyl acetate in hexanes to afford 3,5-dimethyl-2-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol as white solid: 1H NMR (300 MHz, CD3OD): δ 6.93 (m, 2 H), 6.65 (m, 2 H), 5.18 (s, 2 H), 4.05 (s, 2 H), 3.48 (s, 3 H), 3.30 (m, 1 H), 2.41 (s, 3 H), 2.19 (s, 3 H), 1.18 (d, J=6.6 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:5); Rf=0.60.
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.[CH:10]1(I)[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1>CN(C)C(=O)C.[Zn].[Cu]I>[Cl:16][C:17]1[C:22]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: IC1CCCC1
Reactant: Clc1nccnc1Cl
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Clc1nccnc1C1CCCC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a suspension of zinc dust (2.00 g, 30.6 mmol) in N,N-dimethylacetamide (20 mL) was added a mixture of trimethylsilyl chloride and 1,2-dibromoethane (7:5, v/v, 0.95 mL total volume) dropwise over 5 minutes. The mixture was stirred for 15 min before cyclopentyl iodide (5.00 g, 25.5 mmol) was added dropwise over 15 min. This mixture was stirred for an additional 15 min and then was added via syringe over 5 min to a mixture of copper(I) iodide (0.30 g, 1.60 mmol), dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (0.65 g, 0.80 mmol), and 2,3-dichloropyrazine (1.66 mL, 16.0 mmol) in N,N-dimethylacetamide (30 mL) under argon atmosphere. The mixture was heated to 80° C. for 7 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The resulting layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were washed with water (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 2-chloro-3-cyclopentylpyrazine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:20])[CH3:19])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cc(Br)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 4-bromo-2-ethylaniline (50 g, 0.25 mol) in dichloromethane (250 ml) is added triethylamine (63.24 g, 0.62 mol) and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is cooled to 0° C. and acetyl chloride (39.25 g, 0.5 mol) is added dropwise. The reaction mixture is stirred at 25-30° C. for 60 minutes, then poured into water, and the two phases separated. The organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated under reduced pressure to yield N-(4-bromo-2-ethylphenyl)acetamide (40 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[CH:7][C:6]=2[CH:10]=1.[C:11]([O-:14])(=[O:13])C.[Na+].[CH3:16]N(C=O)C>CO.Cl[Pd]Cl>[S:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:11]([O:14][CH3:16])=[O:13])=[CH:10][C:6]=2[CH:7]=[N:8]1
Reactant: CC(=O)[O-]
Reactant: CN(C)C=O
Reactant: Brc1ccc2sncc2c1
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2sncc2c1
Reaction time: 18 h
Yield: 5 %

Procedure:
To a solution of 1.51 g of 5-bromobenzo[d]isothiazole and 825.0 mg of 1,1′-cis(diphenylphosphino)ferrocene]dichloropalladium(II) in 35 mL methanol in a small Parr bottle was added sodium acetate (1.74 g) and DMF (543 μL). The mixture was degassed several times with nitrogen, then shaken under an atmosphere of CO (40 psi) at 50 degrees for 18 hours. The solution was filtered and concentrated. The residue was flash chromatographed (0-20% EtOAc/Haptanes gradient) to yield 61.0 mg (5%) of methyl benzo[d]isothiazole-5-carboxylate as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 3.96 (s, 3 H) 8.17 (d, J=0.98 Hz, 2 H) 8.84 (s, 1 H) 9.08 (s, 1 H); LC-MS @ 194.1 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][Cl:17])[C:11](=[O:18])[CH2:10][C:9]=2[CH:19]=1)[CH2:2][CH3:3].[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1>>[ClH:17].[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][N:21]([CH3:20])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[C:11](=[O:18])[CH2:10][C:9]=2[CH:19]=1)[CH2:2][CH3:3]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CCCOc1ccc2c(c1)CC(=O)N(CCCl)C=C2
Product: CCCOc1ccc2c(c1)CC(=O)N(CCN(C)CCc1ccc(OC)c(OC)c1)C=C2
Product: Cl

Procedure:
This compound was prepared analogous to Example 1(b) from 1-(8-propoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-2-chloro-ethane and N-methyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-amine.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]=[C:10]([CH3:28])[CH2:11][CH2:12][CH:13]=[C:14]([CH:26]=[O:27])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[CH:26](/[C:14](/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:13]/[CH2:12][CH2:11]/[C:10](/[CH3:28])=[CH:9]/[CH2:8][OH:7])=[O:27]
Reactant: CC(C)=CCCC(C)=CCCC(C=O)=CCCC(C)=CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CC/C(C=O)=C\CC/C(C)=C/CO
Reaction time: 8 h

Procedure:
In 100 ml of methanol was dissolved 10.0 g of 7-formyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol tetrahydropyranyl ether prepared in Example 2-(1), and to this solution was added 100 mg of p-toluenesulfonic acid. The mixture was allowed to stand overnight at room temperature and neutralized with an aqueous sodium hydrogencarbonate solution. The methanol was distilled off, and the residue was extracted with ether. (E,E,E)-7-Formyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol obtained from the etheral layer was dissolved in 60 ml of ethanol. After addition of 5.5 g of sodium borohydride under ice-cooling, the solution was vigorously stirred for 2 hours. The mixture was then treated with dilute acetic acid and, after addition of water, extracted with ether. The oil obtained from the ethereal layer was purified by the silica gel column chromatography, yielding 6.6 g of the desired (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol.
Reaction SMILES: C(O)(=O)C(O)=O.C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:49])[CH2:45][CH2:46][CH2:47][CH3:48]>O1CCCC1>[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:49])[CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise valeryl chloride (0.12 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.385 g oil. Crystallization from diethyl ether provided 0.176 g colorless crystals. Mp 107°-109° C. Mass spectrum, m+ =413. Anal (C23H35N5O2) theory C, 66.80; H, 8.53; N, 16.93; found C, 66.59; H, 8.66; N, 17.04.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[CH3:46][O:47][C:48]([N:50]=[C:51]=S)=[O:49].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C1C=CC=CC=1>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:51]([NH:50][C:48]([O:47][CH3:46])=[O:49])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: COC(=O)N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: c1ccccc1
Product: COC(=O)Nc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (145 mg) in a mixture of acetonitrile and benzene [1:4(v/v)] was added methoxycarbonyl isothiocyanate (36 mg) and the reaction mixture was stirred at ambient temperature for 5 minutes. After being added 1,3-dicyclohexylcarbodiimide (73 mg) to the solution, the resulting mixture was stirred at reflux temperature for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (chromatorex) eluting with chloroform and preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-4-(2-methoxycarbonylamino-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (82 mg) as a powder.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].S([O-])(O)=O.[Na+].[CH:28]([C:30]1[O:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=1)=O>O>[C:11]([C:10]1[CH:19]=[CH:20][C:21]2[N:22]=[C:28]([C:30]3[O:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=3)[NH:7][C:8]=2[CH:9]=1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc(C(=O)O)o3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
N,N-Dimethylacetamide (5 ml) was heated to 130° C., and 3,4-diaminobenzophenone (63 mg, 0.30 mmol) and sodium hydrogensulfite (37 mg, 0.36 mmol) were added and the mixture was stirred for 5 minutes. 5-Formyl-furan-2-carboxylic acid (50 mg, 0.36 mmol) was added and stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration to afford 5-(5-benzoylbenzimidazol-2-yl)-furan-2-carboxylic acid (63 mg, 64%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:23][CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:19]([O:18][C:16]([CH:15]1[CH2:21][CH2:22][CH2:23][N:13]([CH2:2][CH:3]2[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]2)[CH2:14]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (3.0 g, 13.09 mmol) and ethyl nipecotate (2.65 ml, 17.02 mmol) in DMF (15 ml) was added DIPEA (7.5 ml). The reaction mixture was irradiated in the microwave reactor at 110° C. for 3 min. Water (20 ml) was then added. The reaction mixture was extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and evaporated to give the crude title compound, which was purified by column chromatography (DCM/MeOH, 95:5).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([C:11](O)=[O:12])[C:3]=1[C:14](O)=[O:15].B>O1CCCC1>[F:1][C:2]1[C:3]([CH2:14][OH:15])=[C:4]([CH2:11][OH:12])[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: OCc1c(F)c(F)c(F)c(F)c1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 10 tetrahydrofuran (THF) is added 3,4,5,6-tetrafluoro-1,2-benzenedicarboxylic acid (2 g, 8.4 mmol). After cooling at 0°, 21.0 ml (20.9 mmol) of 1 M borane in THF is slowly added. The reaction mixture is allowed to rise to RT and stirred at RT for 18 hours and then is cooled and quenched with 10% HCl. The reaction mixture is added to ether, and the organic phase is washed with water, sat. sodium bicarbonate and brine, dried over sodium sulfate and evaporated under vacuum to yield 3,4,5,6-tetrafluoro-1,2-bis(hydroxymethyl)benzene.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(Br)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Temperature: 130 °C
Yield: 71 %

Procedure:
(see Kido, J.; Su, S. -J.; Sasabe, H.; Takeda, T.; Chem. Mater. 2008, 20(5), 1691-1693, which is incorporated by reference herein for its relevant teachings) was prepared as follows: a mixture of carbazole (4.000 g, 23.92 mmol), 1,3-dibromobenzene (14.11 g, 59.81 mmol), K2CO3 (9.919 g, 71.77 mmol), copper powder (4.561 g, 71.77 mmol) and anhydrous N,N-dimethylformamide (DMF) (120 mL) was degassed with argon for 1 h. while stirring. The reaction mixture was then maintained under argon at 130° C. while stirring for 4 days until TLC (SiO2, 4:1 hexanes-dichloromethane) indicated consumption of the starting material. Upon cooling to RT, about 300 mL dichloromethane was added, the crude mixture filtered, the filtrant wash with an additional 200 mL dichloromethane, and the filtrate concentrated in vacuo. The resulting residue was then purified by flash chromatography (SiO2, hexanes) to yield Compound 3 (5.47 g, 71%) as a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH2:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([N:39]=[C:40]=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>[F:27][C:28]([F:42])([F:43])[C:29]1[CH:30]=[C:31]([NH:39][C:40](=[O:41])[N:11]([CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH2:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[CH:15][CH:14]=2)[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=1
Reactant: CC(C)(C)C1CCC(NCc2ccc(C(O)Cc3nn[nH]n3)cc2)CC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(O)Cc3nn[nH]n3)cc2)C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Resin bound 1-{4-[(4-tert-butylcyclohexylamino)methyl]phenyl}-2-(2H-tetrazol-5-yl)ethanol (50 mg) was suspended in DCP (500 μl) and N,O-bis(trimethylsilyl)acetamide (100 μl) was added. The mixture was shaken at room temperature for 1 hour, then a solution of 3,5-bis(trifluoromethyl)phenylisocyanate (48 mg, 0.19 mmol) in DCP (500 μl) was added. The resin mixture was shaken overnight at room temperature, then drained and washed with DCM (3×2 ml); DMF (3×2 ml); water (2×2 ml, each 20 min washes), THF (3×2 ml) and finally DCM (6×2 ml). The resin was then treated with 50% TFA in DCM for 30 min. Solvent was collected by filtration, and taken to dryness by evaporation in vacuo.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(CC(=O)C)(=O)C.Br[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:21](=[O:22])[O:20][CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>[Cu](Br)Br.O.CN(C=O)C>[O:7]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:21](=[O:22])[O:20][CH2:19]2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: Oc1ccccc1
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCc2cc(Oc3ccccc3)ccc21
Yield: 72 %

Procedure:
A reactor was charged with DMF (68 Kg), and stirring was initiated. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromophthalide (85 Kg), copper bromide (9 Kg), and potassium carbonate (77 Kg). The mixture was heated above 85° C. and maintained until reaction completion and then cooled. Water was added. Solid was filtered and washed with water. Solid was dissolved in dichloromethane, and washed with aqueous HCl and then with water. Solvent was removed under pressure and methanol was added. The mixture was stirred and filtered. Solid was washed with methanol and dried in an oven giving 5-phenoxyphthalide (Yield: 72%, HPLC: 99.6%).
Reaction SMILES: [CH3:1][N:2]([CH2:17][C:18]([O:20]CC)=O)[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:5])=[O:4].[OH-].[NH4+:24]>>[OH2:4].[CH3:1][N:2]([CH2:17][C:18]([NH2:24])=[O:20])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:5])=[O:4]
Reactant: CCOC(=O)CN(C)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reactant: [NH4+]
Agent: [OH-]
Product: CN(CC(N)=O)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Product: O
Temperature: 40 °C

Procedure:
In this example, 3.39 g of ethyl (N-methyl-3-trifluoromethylbenzylsulfonamido)acetate was ground to a powder and combined with about 50 ml of ammonium hydroxide at room temperature. The reaction mixture was heated to about 40° C. and maintained at this temperature for about three hours. The precipitate was collected, washed with water and triturated with ethyl ether to afford 1.4 g of white solid; m.p. 156° to 159° C.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5](/[Mg]Br)=[CH:6]\[CH3:7].[Si:10]([O:17][CH2:18][C@@H:19]([N:25]([CH2:33][C:34](N(OC)C)=[O:35])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:20]([CH:22]1[CH2:24][CH2:23]1)=[CH2:21])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1>[Si:10]([O:17][CH2:18][C@@H:19]([N:25]([CH2:33][C:34](=[O:35])[CH:5]=[CH:6][CH3:7])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:20]([CH:22]1[CH2:23][CH2:24]1)=[CH2:21])([C:13]([CH3:15])([CH3:14])[CH3:16])([CH3:12])[CH3:11]
Reactant: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: C/C=C/[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C=CC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A suspension of cerium (III) chloride (27.8 g, 112.95 mmol) in THF (100 mL) at room temperature was stirred vigorously for 2 hours. The suspension was cooled to −78° C. and (E)-prop-1-enylmagnesium bromide (0.5 M in THF) (226 mL, 112.95 mmol) was added dropwise. The mixture was stirred at −78° C. for 1.5 hours. (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 235, 5 g, 11.30 mmol) in THF (20 mL) was then added dropwise at −78° C. The reaction was stirred at −78° C. for 30 minutes and then warmed to 0° C. for 15 minutes. The reaction was quenched with 10% citric acid, diluted further with water and extracted twice with ether. The organics were washed once with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound as a light yellow oil (4.0 g, 84%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26](N[C@H](C#C)CC(O)=O)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.[NH:37]1[CH2:46][CH2:45][CH:40]([C:41]([O:43]C)=[O:42])[CH2:39][CH2:38]1>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([N:37]2[CH2:46][CH2:45][CH:40]([C:41]([OH:43])=[O:42])[CH2:39][CH2:38]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C1CCNCC1
Reactant: C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCN(S(=O)(=O)c2cccc(OCCCCNc3ccccn3)c2)CC1

Procedure:
The procedure for the preparation of the product of EXAMPLE 17 was repeated using methyl isonipecotate (Aldrich) in the place of ethyl (3S)-3-aminopent-4-ynoate hydrochloride to provide the title product. 1H (CD3OD): δ 7.86 (1H, d); 7.61 (1H, t); 7.49 (1H, t); 7.32 (1H, d); 7.24 (1H, s); 7.20 (1H, d); 6.74 (1H, d); 6.66 (1H, t); 4.12 (2H, t); 3.57 (2H, br. d); 3.37 (2H, t); 2.52 (2H, t); 2.27 (1H, tt); 1.94 (4H, m); 1.84 (2H, p); 1.71 (2H, br. q).